Derangements of cerebral blood flow (CBF) are frequently responsible for brain damage at the time of birth. Yet much remains to be learned about developmental influences on the regulation of CBF. We will concentrate on cerebrovascular responses to hypoxia and on cerebral autoregulation in fetal, newborn and adult sheep. The relationship between cerebral O2 consumption (m/100g/min) and the total O2 delivered to the brain (ml/100g/min) is not the same in the fetus as after birth. Further, responses to hypoxic hypoxia differ between fetus and adult. We have shown that cerebral O2 delivery is in part a function of oxyhemoglobin affinity. We will see if differing responses to hypoxia are also dependent on oxyhemoglobin affinity. We hope to use our data on hypoxic cerebrovascular responses to answer some basic physiological questions. We hope we will be able to formulate an inclusive hypothesis predicting cerebrovascular response to hypoxia. In order to do this we need to assess the independent contribution of the fall in hematocrit in anemia. We will compare anemia with methemoglobinemia, in which the fall in O2 content is not accompanied by a hematocrit change. We will also consider mechanisms of hypoxic cerebrovascular dilation. We have shown that drugs which share the property of inhibiting tissue oxygenases virtually abolish cerebral vasodilation to hypoxia in the dog. We will study these compounds in sheep, especially in the "hypoxic" fetus. We will continue studies of cerebral autoregulation in newborn and adult sheep using a newly described pulsed-Doppler technique for continuous monitoring of blood velocity in individual vessels. We can for the first time compare the speed of autoregulation in immature and adult animals. We intend to discover the effects of intraventricular blood on the cerebrovascular bed. We have sufficient experience with our model to feel that perturbations in cerebrovascular responses can be identified. Such data are important to the discovery of mechanisms for brain damage with intraventricular hemorrhage in premature infants.